Breast cancer prevention by short-term inhibition of TGFβ signaling

Author:

Alečković MašaORCID,Cristea Simona,Gil Del Alcazar Carlos R.,Yan Pengze,Ding Lina,Krop Ethan D.,Harper Nicholas W.,Rojas Jimenez Ernesto,Lu Donghao,Gulvady Anushree C.,Foidart Pierre,Seehawer Marco,Diciaccio Benedetto,Murphy Katherine C.ORCID,Pyrdol Jason,Anand Jayati,Garza Kodie,Wucherpfennig Kai W.ORCID,Tamimi Rulla M.,Michor FranziskaORCID,Polyak KorneliaORCID

Abstract

AbstractCancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFβ in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.

Funder

U.S. Department of Health & Human Services | NIH | National Cancer Institute

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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